What are the 4 targets of antibiotic targets?
- Damaging the cell wall/membrane
Cell wall synthesis inhibitors
Drugs that damage cell membranes
- Inhibitors of protein synthesis
- Inhibitors of RNA
RNA polymerase inhibitors
- Inhibitors of DNA
DNA gyrase inhibitors
Inhibitors of purine synthesis
Inflict DNA damage
How is susceptibility determined?
What is minimum inhibitory concentration (MIC)?
What is bactericidal concentration (MBC)?
Bacteria are isolated then incubated with various antibiotics to determine sensitivity
Minimum inhibitory concentration (MIC)- lowest concentration of antimicrobial that prevents bacterial growth after incubation (18-24 hours)
Minimum bactericidal concentration (MBC)- minimum concentration of antimicrobial that kills 99.9% of cells after incubation
What is concentration dependant killing?
Some antibiotics exhibit this which means the higher their concentration, the faster the bacteria is killed off
Ex : fluoroquinolones
Also exhibit a post antibiotic effect, meaning they continue to inhibit bacterial growth even after the concentrations of drug fall below the MIC
What are 3 things we consider when choosing an antibiotic for a given patient?
- Route of administration- oral vs intravenous
- Adverse effects- allergies, specific contraindications
- Pharmacokinetics- do they patients have sufficient kidney function to eliminate a renally eliminated drug?
How does antibiotic use change in pregnancy?
Some antibiotics are not considered safe to use in pregnancy (can be based on trimester)
Tetracyclines will chelate calcium, which reduces calcium available to the developing fetus, resulting in impaired development of bones
Trimethoprim (TMP) inhibits formation of THF which interferes with endogenous folate levels (folate important for normal early development)
What is the protein synthesis inhibitor antifungal antimicrobial?
Analogous to the ribosomal inhibitors found in antibacterials
Used topically to treat fungal infections of the toenail
What is the antimicrobial chitin synthesis inhibitor?
Fungal wall synthesis inhibitors currently target glucan, to weaken the cell wall Cell walls are also composed of chitin Antifungals Chitin synthesis inhibitor: nikkomycins Currently in development
What’s another antifungal method being researched?
Collapse fungal cell mitochondria to deplete energy
What area do we have the fewest effective antibiotics in?
Gram negative bacteria
Also focus on BAM- plays a key role in outer membrane synthesis
How does research in antibiotics find new ways to get old drugs across the outer membrane?
Cephalosporin bound to catechol group, catechol group chelates iron
Because the bacteria has iron transporter, the drug easily moves through the outer membrane, reaching its target
Will we run out of target to exploit with antibiotics?
Yes, there are only so many bacterial/fungal targets to exploit
Therefore we need to consider new approaches to treating infections caused by bacteria/fungi (that don’t involve the current paradigm and don’t involve same steps in drug discovery)
What is the theory that we can disarm the bug?
Remove/inhibit the virulence factors produced by the bacteria/fungi
Trehalose is a virulence factor released by a number of fungi
Nanoparticles- design these that are able to seek out and damage bacterial cells or deliver antibiotics to targets in cell
What is phage therapy?
Back to the future
Phages are naturally occurring viruses that infect bacteria
Phage therapy was once popular
Now that we are desperate it’s coming back